In obesity, skeletal muscle mitochondrial activity changes to cope with increased nutrient availability. Autophagy has been proposed as an essential mechanism involved in the regulation of mitochondrial metabolism. Still, the contribution of autophagy to mitochondrial adaptations in skeletal muscle during obesity is unknown. Here, we show that in response to high-fat diet (HFD) feeding, distinct skeletal muscles in mice exhibit differentially regulated autophagy that may modulate mitochondrial activity. We observed that after 4 and 40 weeks of high-fat diet feeding, OXPHOS subunits and mitochondrial DNA content increased in the oxidative soleus muscle. However, in gastrocnemius muscle, which has a mixed fiber-type composition, the mitochondrial mass increased only after 40 weeks of HFD feeding. Interestingly, fatty acid-supported mitochondrial respiration was enhanced in gastrocnemius, but not in soleus muscle after a 4-week HFD feeding. This increased metabolic profile in gastrocnemius was paralleled by preserving autophagy flux, while autophagy flux in soleus was reduced. To determine the role of autophagy in this differential response, we used an autophagy-deficient mouse model with partial deletion of Atg7 specifically in skeletal muscle (SkM-Atg7^+/− mice). We observed that Atg7 reduction resulted in diminished autophagic flux in skeletal muscle, alongside blunting the HFD-induced increase in fatty acid-supported mitochondrial respiration observed in gastrocnemius. Remarkably, SkM-Atg7^+/− mice did not present increased mitochondria accumulation. Altogether, our results show that HFD triggers specific mitochondrial adaptations in skeletal muscles with different fiber type compositions, and that Atg7-mediated autophagy modulates mitochondrial respiratory capacity but not its content in response to an obesogenic diet.

中文翻译：

---

骨骼肌类型特异性线粒体对高脂肪饮食的适应依赖于差异自噬调节


在肥胖症中，骨骼肌线粒体活性发生变化，以应对营养可用性的增加。自噬已被认为是参与线粒体代谢调节的重要机制。尽管如此，自噬对肥胖期间骨骼肌线粒体适应的贡献尚不清楚。在这里，我们发现，为了响应高脂肪饮食（HFD）喂养，小鼠不同的骨骼肌表现出差异调节的自噬，可能调节线粒体活性。我们观察到，高脂饮食喂养 4 周和 40 周后，氧化比目鱼肌中 OXPHOS 亚基和线粒体 DNA 含量增加。然而，在具有混合纤维型成分的腓肠肌中，线粒体质量仅在 HFD 喂养 40 周后才增加。有趣的是，在 4 周的 HFD 喂养后，腓肠肌中由脂肪酸支持的线粒体呼吸增强，但比目鱼肌中则没有增强。腓肠肌代谢特征的增加与自噬通量的保持相平行，而比目鱼肌的自噬通量则减少。为了确定自噬在这种差异反应中的作用，我们使用了一种自噬缺陷小鼠模型，其中 Atg7 部分缺失，特别是在骨骼肌中（SkM-Atg7 ^+/-小鼠）。我们观察到 Atg7 的减少导致骨骼肌中自噬通量减少，同时减弱了 HFD 诱导的腓肠肌中观察到的脂肪酸支持的线粒体呼吸的增加。值得注意的是，SkM-Atg7 ^+/-小鼠并未表现出线粒体积累增加。 总而言之，我们的结果表明，HFD 会触发具有不同纤维类型组成的骨骼肌中的特定线粒体适应，并且 Atg7 介导的自噬调节线粒体呼吸能力，但不会调节其对肥胖饮食的反应。